Pfizer, Inc., Groton, Connecticut, USA.
Pfizer, Inc., New York, New York, USA.
Clin Pharmacol Drug Dev. 2021 Nov;10(11):1297-1306. doi: 10.1002/cpdd.970. Epub 2021 Jul 2.
Ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for treatment of type 2 diabetes. Two population pharmacokinetic (PK) analyses were conducted, using data from up to 17 phase 1 to 3 studies, to characterize ertugliflozin PK parameters in select ethnic subgroups: (1) East/Southeast (E/SE) Asian vs non-E/SE Asian subjects; (2) Asian subjects from mainland China vs Asian subjects from the rest of the world and non-Asian subjects. A 2-compartment model with first-order absorption, lag time, and first-order elimination was fitted to the observed data. For the E/SE Asian vs non-E/SE Asian analysis (13 692 PK observations from 2276 subjects), E/SE Asian subjects exhibited a 17% increase in apparent clearance (CL/F) and 148% increase in apparent central volume of distribution (Vc/F) vs non-E/SE Asian subjects. However, individual post hoc CL/F values were similar between groups when body weight differences were considered. For the second analysis (16 018 PK observations from 2620 subjects), compared with non-Asian subjects, CL/F was similar while Vc/F increased by 44% in Asian subjects from mainland China and both CL/F and Vc/F increased in Asian subjects from the rest of the world (8% and 115%, respectively) vs non-Asian subjects. Increases in Vc/F would decrease the ertugliflozin maximum concentration but would not impact area under the concentration-time curve. Therefore, the differences in CL/F (area under the concentration-time curve) and Vc/F were not considered clinically relevant or likely to result in meaningful ethnic differences in the PK of ertugliflozin.
依格列净是一种钠-葡萄糖共转运蛋白 2 抑制剂，获批用于治疗 2 型糖尿病。进行了两项群体药代动力学（PK）分析，共纳入多达 17 项 1 期至 3 期研究的数据，以确定依格列净在特定种族亚组中的 PK 参数特征：（1）东亚/东南亚（E/SE）亚洲人与非 E/SE 亚洲人；（2）中国大陆亚洲人与世界其他地区和非亚洲人的亚洲人。采用具有一级吸收、滞后时间和一级消除的两室模型对观察到的数据进行拟合。在 E/SE 亚洲人与非 E/SE 亚洲人分析（来自 2276 名受试者的 13692 个 PK 观察值）中，E/SE 亚洲人表现出表观清除率（CL/F）增加 17%，表观中央分布容积（Vc/F）增加 148%，而非 E/SE 亚洲人。然而，当考虑体重差异时，两组间的个体事后 CL/F 值相似。在第二项分析（来自 2620 名受试者的 16018 个 PK 观察值）中，与非亚洲人相比，CL/F 相似，而中国大陆亚洲人的 Vc/F 增加 44%，世界其他地区的亚洲人 CL/F 和 Vc/F 均增加（分别为 8%和 115%），而非亚洲人。Vc/F 的增加会降低依格列净的最大浓度，但不会影响浓度-时间曲线下面积。因此，CL/F（浓度-时间曲线下面积）和 Vc/F 的差异不被认为具有临床意义，也不太可能导致依格列净 PK 方面存在有意义的种族差异。
